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Tetrahedron 70 (2014) 2919e2927

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Tetrahedron

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New synthesis of idraparinux, the non-glycosaminoglycan analogueof the antithrombin-binding domain of heparin

Mih�aly Herczeg a, Erika Mez}o a,b, D�aniel Eszenyi a,b, S�andor Antus a, Anik�o Borb�as b,*

aDepartment of Organic Chemistry, University of Debrecen, H-4010 Debrecen, PO Box 20, HungarybDepartment of Pharmaceutical Chemistry, Medical and Health Science Center, University of Debrecen, H-4010 Debrecen, PO Box 70, Hungary

a r t i c l e i n f o

Article history:Received 4 January 2014Received in revised form 24 February 2014Accepted 11 March 2014Available online 15 March 2014

Keywords:AnticoagulationHeparinoid pentasaccharideGlycosylation reactionsOrthogonal protecting groupsMultiple functionalizationUronic acids

* Corresponding author. Tel.: þ36 52512900/22475addresses: borbas.aniko@pharm.unideb.hu, borbas.Borb�as).

0040-4020/$ e see front matter � 2014 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2014.03.033

a b s t r a c t

Idraparinux, the fully O-sulfated, O-methylated, heparin-related pentasaccharide possessing selectivefactor Xa inhibitory activity, was prepared by a new synthetic pathway. This route was based on a [2þ3]block synthesis utilizing a 6-O-silyl-protected L-idose-containing trisaccharide acceptor, which wasglycosylated with a disaccharide donor containing a non-oxidized precursor of the glucuronic acid. Theunique strategy of multiple functionalizations at pentasaccharide levels, involving triple methylationfollowed by oxidation of the glucose and the idose precursors into D-glucuronic and L-iduronic acids inone step, proved to be highly efficient, providing the target pentasaccharide through a 39-step synthesisstarting from D-glucose and methyl a-D-glucopyranoside.

� 2014 Elsevier Ltd. All rights reserved.

Fig. 1. The specific antithrombin-binding DEFGH pentasaccharide unit of heparin (1)

1. Introduction

Heparin is a complex, highly sulfated natural polysaccharidethat has been used as an anticoagulant formore than seven decadesin a broad range of clinical thrombotic conditions.1 Heparin dis-plays anticoagulant activity through activation of antithrombin,a serine protease inhibitor that blocks thrombin and, to a lesserextent, factor Xa in the blood-coagulation cascade.2 Fondaparinux(2) is a synthetic analogue of the antithrombin-binding DEFGHdomain of heparin (1), which exclusively potentiates the anti-factorXa activity of antithrombin and has no effect on thrombin (Fig. 1).3

Fondaparinux (Arixtra, GlaxoSmithKline) provided the proof ofprinciple that selective inhibition of the specific coagulation en-zyme factor Xa could afford clinically effective anticoagulation.4

Idraparinux (3)3b,5 is an analogue of fondaparinux inwhich theN-sulfates are replaced by O-sulfates and the hydroxyl groups aremethylated. Idraparinux binds to AT significantly stronger thanfondaparinux through hydrophobic interactions and also exhibitssuperior anti-Xa-activity anda longerhalf-life allowingonce-a-weekadministration. Although the antithrombotic efficacy in men wasproven in clinical studies, the development of idraparinux wasstopped due to major bleeding events during treatment for more

and its synthetic analogues fondaparinux (2) and idraparinux (3).

; fax: þ36 52512914; e-mailaniko@science.unideb.hu (A.

All rights reserved.

than six months.6 Notwithstanding, the feasible synthesis and spe-cific activitymake idraparinux a potential lead andan ideal referencecompound for further development of selective factor Xa inhibitors.

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e29272920

In the frame of our ongoing research aimed at the synthesis ofsulfonic acid-containing heparinoid anticoagulants,7e11 idrapar-inux is planned to be applied as a reference compound in STD NMRand competition STD titration experiments to investigate thebinding specificity and activity of the pentasaccharide sulfonic acidderivatives against antithrombin. To provide a sufficient amount of3 for the NMR binding studies, an efficient synthesis is required.

One of the most challenging feature of the target structure is thepresence of methyl ethers at the uronic acid residues, which areprone to suffer b-elimination in the basic conditions of the ether-ification. In this context, prior syntheses of 3 followed two differentstrategies.5,12,13 In the first approach, the methyl ethers were in-troduced into the non-oxidized precursors of the uronic acids ata monosaccharide level, and formation of the uronic acids wasachieved at disaccharide levels.5,12 This method, elaborated byWesterduin et al. in 1994 and also applied by Chinese authors 15years later, had the drawback that the partially methylated

Scheme 1. Synthesis of the L-idose-containing disaccharide acceptor 7. Reagents and conditions: (a) CH2Cl2, TMSOTf, �40 to �10 �C, 2 h; (b) H2O, TFA, 0 �C to rt, 3 h, 73% for twosteps; (c) py, TBDMSCl, 24 h, 96%.

monosaccharide building blocks were achieved via lengthy multi-step processes, and overall syntheses of 3 required more than 50steps from commercially available starting monosaccharides. In theother approach, published by our group, three of the methyl ethersof the uronic acid residues were introduced in one step at a pen-tasaccharide level, hence, the length of the procedure could bereduced to 41 synthetic steps. The weakness of this strategy wasthat the base-sensitivity of the uronic acid residues did not allowthe usual sodium hydride mediated etherification. Therefore,freshly prepared silver(I) oxide was used to assist the methylationthat, however, showed moderate efficacy.

We envisioned an improved route to 3, combining the strengthsof the above two strategies. Hence, we decided to accomplish thesynthesis by assembling a pentasaccharide containing non-oxidized precursor of the uronic acids followed by introduction ofthree methyl ethers in one step at a pentasaccharide level by effi-cient sodium hydride mediated methylation, and subsequent oxi-dation of the two uronic acid precursors in one step. Through thispathway, the inefficient glycosylations with the uronic acid build-ing blocks of inherent low reactivity observed in earlier synthe-sis,5,12,13 could also be avoided. Herein, synthesis of idraparinux bythis novel strategy is described.

2. Results and discussion

The synthesis of the fully O-sulfated, O-methylated penta-saccharide 3 was planned by condensation of a FGH trisaccharideacceptor containing the non-oxidized precursor of the L-iduronic

acid, and a DE disaccharide donor containing the non-oxidizedprecursor of the D-glucuronic acid. The hydroxyls to be methyl-ated were masked in the form of acetates, whereas benzyl groupswere introduced to mask the hydroxyls that were to be sulfated.This protecting group strategy also ensures the stereocontrol in theglycosylation steps.

The L-idopyranosyl donor 4, useful for the synthesis of the FGHtrisaccharide unit has been described recently as a building blockfor heparinoid sulfonic acids.11,14 Condensation of donor 4 and ac-ceptor 515 in the presence of trimethylsilyl triflate (TMSOTf), andsubsequent removal of the benzylidene acetal ring by acidic hy-drolysis furnished the a-linked disaccharide diol 6 in 73% yield overtwo steps. To protect the primary hydroxyl that is to be oxidized ata pentasaccharide level, a silyl ether was chosen because of its or-thogonality both to the acetyl and the benzyl protecting groups.17

Therefore, tert-butyldimethylsilyl (TBDMS) group was installed tothe primary position of 6 to provide 7 in 96% yield (Scheme 1).

The fully protected thioglucoside 9, serving as a glycosyl donorfor the synthesis of the FGH trisaccharide acceptor, was prepared bybenzylation of 816 possessing a selectively removable 4-O-(2-naphthyl)methyl protecting group. Surprisingly, glycosylation ofacceptor 7with donor 9 in the presence of N-iodosuccinimide (NIS)and TfOH led to the formation of a plethora of products. Besides thedesired trisaccharide 10 in a 9% yield, cleavage of the tert-butyldi-methylsilyl group of the L-idose unit also occurred affording 11 in49% yield and also leading to further side reactions to give mono-saccharide 12 and tetrasaccharide 13, both isolated as anomericmixtures.

To avoid the loss of the tert-butyldimethylsilyl group, mediatedby the acid catalyst of the coupling reaction, condensation of 7 and9was carried out again in the presence of sym-collidine. Due to thebuffering effect of the hindered base, the side reactions could besuppressed and the glycosylation reaction provided the fully pro-tected trisaccharide 10 in 71% yield (Scheme 2).

Despite the success of the above glycosylation reaction, we de-cided to accomplish the synthesis of the FGH trisaccharide buildingblock by changing the tert-butyldimethylsilyl moiety to the tert-butyldiphenylsilyl (TBDPS) protecting group. TBDPS has two mag-nitude higher stability under acidic conditions then TBDMS,17 andwe expected that this higher stability might give rise to higherglycosylation efficacy throughout the synthesis of 3. Hence, thedisaccharide diol 6 was treated with tert-butyldiphenylsilyl chlo-ride in pyridine to provide acceptor 14, glycosylation of which withdonor 9 furnished smoothly, the required trisaccharide 15 in 77%yield (Scheme 3).

Scheme 2. Synthesis of the fully protected FGH trisaccharide 10 bearing TBDMS- and NAP-ethers as orthogonal protecting groups. Reagents and conditions: (a) NaH, BnBr, DMF,93%; (b) CH2Cl2, NIS, TfOH, �40 to �10 �C, 2 h, 9% for 10, 49% for 11, 15% for 12, 24% for 13; (c) CH2Cl2, NIS, AgOTf, sym-collidine, �40 to 10 �C, 3 h, 71% for 10.

Scheme 3. Synthesis of the orthogonally protected FGH trisaccharide possessing 6-O-TBDPS group at the L-idose unit. Reagents and conditions: (a) TBDPSCl, py, rt, 24 h, 92%;(b) CH2Cl2, NIS, AgOTf, �40 to �10 �C, 2 h, 77%.

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927 2921

Next, trisaccharides 16 and 18, useful as acceptors for theplanned [DEþFGH] couplings, were prepared (Scheme 4). Selectivedemasking of the 4-OH group of the terminal glucose unit of both10 and 15 by cleavage of the 2-naphthylmethyl (NAP) ether with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)18 furnished di-rectly the glycosyl acceptors 16 and 18, respectively, however, withsignificantly different yields. While efficient oxidative removal ofthe NAP-group was observed in the presence of the TBDPS-ether

Scheme 4. Synthesis of trisaccharide acceptors 16 and 18. Reagents and conditions: (a)CH2Cl2, H2O, DDQ, rt, 30 min, 47% for 16, 69% for 17, 74% for 18; (b) TBDPSCl, py, rt, 24 h,82%.

(15/18, 74%), transformation of the TBDMS-containing 10 into16 proceeded in only 47% yield that could be explained, again, withthe moderate stability of the TBDMS-ether under acidic conditions.During the reaction, a hydroquinone derivative was formed fromthe reagent, the acidity of which led to partial cleavage of theTBDMS group. Trisaccharide 11, one of the by-products of the 7þ9coupling was also transformed to acceptor 18 via removal of theNAP-ether (11/17) followed by selective silylation of the primaryhydroxyl of the L-idose unit with tert-butyldiphenylsilyl chloride.

Compound 19,10 prepared recently by our group to heparinoidsulfonic acids, was chosen as the non-glucuronide type donorbearing a (2-naphthyl)methyl group to temporarily protect thehydroxyl destined to be oxidized. Condensation of disaccharide 19and the trisaccharide acceptors 16 or 18 upon NISeAgOTf activa-tion, provided the needed pentasaccharides 20 and 21, respectively.As we expected, a significantly higher yield was achieved with theTBDPS-protected trisaccharide 18 compared to its TBDMS-counterpart 16 (Scheme 5).

The synthesis was continued with the TBDPS-containing pen-tasaccharide 21 of which we had a sufficient amount for theremaining transformations. First, compound 21 was subjected toZempl�en deacetylation to produce triol 22 (Scheme 6). Introductionof the methyl ethers to the liberated hydroxyls was accomplishedby standard alkylation using methyl iodide and sodium hydride toafford the desired compound 23 in a rapid reaction in 85% yield. It isworth mentioning that our previous approach to idraparinux in-volved a triple methylation step at the pentasaccharide level in thepresence of uronic acids. That reaction was assisted by silver(I)

Scheme 5. Synthesis of the pentasaccharide skeleton. Reagents and conditions: (a)CH2Cl2, NIS, AgOTf, �40 to þ5 �C, 3 h, 58% for 20, 76% for 21.

Scheme 6. Novel route to 3 involving simultaneous introduction of three methylethers followed by simultaneous formation of two carboxylic functions at a penta-saccharide level. Reagents and conditions: (a) MeOH, NaOMe, rt, 24 h, 79%; (b) DMF,NaH, MeI, 0 �C to rt, 3 h, 85%; (c) CH2Cl2, H2O, DDQ, rt, 30 min, 71%; (d) THF, Bu4NF, rt,72 h, 96%; (e) CH2Cl2, H2O, TEMPO, BAIB, 0 �C to rt, 24 h, 94%; (f) EtOH, AcOH, 10%Pd(C), 10 atm, H2, rt, 24 h, 91%; (g) SO3/Et3N, DMF, 50 �C, 24 h, 78%.

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e29272922

oxide because of base-sensitivity of the uronide residues, and itrequired a long reaction time of 2 days and showed moderate ef-ficacy to produce the desired product in only 51% yield.

Next, the primary hydroxyls that were to be oxidized were lib-erated in two steps involving oxidative cleavage of the NAP etherwith DDQ followed by removal of the TBDPS ether with tetrabutylammonium fluoride (TBAF). Both deprotection procedures showedgood selectivity to provide diol 25 in 68% overall yield. The twocarboxylic functions were formed by (2,2,6,6-tetramethylpiperidin-1-yl)oxyl TEMPO-based oxidation using [bis(acetoxy)iodo]benzene(BAIB) as co-oxidant,19 affording the disodium salt 26, which wasready for the final two transformations. The seven hydroxyls to besulfated were deprotected by catalytic hydrogenolysis. Sub-sequently, simultaneous O-sulfation of the liberated hydroxyls wasachieved in one step using excess SO3$Et3N to give, after treatmentwith Dowex Naþ ion-exchange resin, the target compound 3 in 78%yield (Scheme 6).

3. Conclusion

In prior syntheses of 3, the uronic acid units were prepared in-dependently at the mono- or disaccharide levels. Our novel ap-proach was based on the synthesis of the pentasaccharide byutilizing non-oxidized precursors of the uronic acids, and theiroxidation in one step at the pentasaccharide level. By this strategy,not only could the synthesis be shortened, but the glycosylationefficacy, which was decreased in previous methods by the inherentlow reactivity of the uronic acid residues, could also be enhanced.

Out of the two applied silyl protecting groups, the tert-butyl-diphenylsilyl-ether proved to be better than the tert-butyldime-thylsilyl-ether to temporarily protect the primary position of the L-idose unit, because of its higher stability under acidic conditions.

Introduction of threemethyl ethers and simultaneous formationof two carboxylic functions at the pentasaccharide level proceededwith high yields, and the target pentasaccharide could be achieved

in a 39-step synthesis using the commercially available D-glucoseand methyl a-D-glucopyranoside as the starting materials.

4. Experimental

4.1. General information

Optical rotations were measured at room temperature witha PerkineElmer 241 automatic polarimeter. TLC was performed onKieselgel 60F254 (Merck) plates with detection by immersing into5% ethanolic sulfuric acid solution followed by heating. Columnchromatography was performed on Silica gel 60 (Merck0.063e0.200 mm) and Sephadex G-25 (SigmaeAldrich, Bead size25e100 mm). Organic solutions were dried over MgSO4, and con-centrated in vacuum. The 1H NMR (360 MHz) and 13C NMR(90.54 MHz) spectra were recorded with Bruker DRX-360 spec-trometer at 25 �C. Chemical shifts are referenced to Me4Si or DSS(0.00 ppm for 1H) and to the solvent signals (CDCl3: 77.00 ppm,CD3OD: 49.15 ppm for 13C). IR spectra were recorded on a Per-kineElmer 16 PC FTIR spectrometer. MALDI-TOF MS analyses of thecompounds were carried out in the positive reflectron mode usinga BIFLEX III mass spectrometer (Bruker, Germany) equipped withdelayed-ion extraction. The matrix solution was a saturated 2,4,6-trihydroxy-acetophenone (THAP) solution in MeCN. Elementalanalyses (C, H, S) were performed using an Elementar VarioMicroCube instrument.

4.2. Methyl (2-O-acetyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (6)

To a solution of acceptor 515 (5.580 g, 11.90 mmol) and donor 414

(4.400 g, 9.50 mmol) in dry CH2Cl2 (250 mL), 4 �A molecular sieves(4.00 g) were added. The stirred mixture was cooled to �40 �Cunder argon. After 30 min at this temperature, TMSOTf (215 mL,1.190 mmol) in CH2Cl2 (5.0 mL) was added. After stirring at �10 �Cfor 2 h, Et3N (500 mL) was added and the reaction mixture wasconcentrated. The crude product was dissolved in a mixture ofCH2Cl2 (170 mL) and H2O (7.68 mL), and F3CCOOH (14.96 mL) wasadded at 0 �C. After the reaction had been completed (3 h), themixture was neutralized with aqueous solution of NaHCO3(16.320 g), diluted with CH2Cl2 (400 mL), washed with satd aqNaHCO3 (2�150 mL) and H2O (2�100 mL), dried and concentrated.The crude product was purified by silica gel chromatography (9:1CH2Cl2/acetone) to give 6 (4.698 g, 73% for two steps) as a colourlesssyrup; [a]D25 �8.9 (c 0.12, CHCl3); Rf 0.45 (9:1 CH2Cl2/acetone); IRnmax (KBr): 3464, 3087, 3063, 3030, 2933, 2369, 2349, 2318, 2246,1737, 1496, 1454, 1371, 1320, 1234, 1167, 1103, 1027, 911, 739, 698,609, 466, 418 cm�1; 1H NMR (CDCl3, 360 MHz): d¼7.34e7.25 (m,15H, arom), 5.08e4.50 (m, 9H, 3�CH2Ph, H-1, H-10, H-20), 4.27e4.24(m, 1H), 3.98e3.84 (m, 2H), 3.77e3.72 (m, 2H), 3.65e3.57 (m, 2H),3.52e3.49 (m, 4H), 3.39e3.27 (m, 5H), 3.12e3.09 (m, 1H),2.65e2.62 (m, 1H), 1.99 (s, 3H, AcCH3), 1.69 (s, 1H, OH) ppm; 13CNMR (CDCl3, 90 MHz): d¼169.3 (CO), 138.2, 137.8, 137.7 (3C, 3�Cqarom), 128.3e127.3 (15C, arom), 97.8, 96.8 (C-1, C-10), 80.2, 80.0,77.4, 72.7, 70.0, 67.7, 66.5, 66.2 (8C, skeleton carbons), 75.9, 73.2,73.0 (3C, 3�CH2Ph), 68.2 (C-6), 62.4 (C-60), 57.9 (C-30-OCH3), 55.0(C-1-OCH3), 20.8 (AcCH3) ppm;MALDI-TOF (positive ion):m/z calcdfor [MþNa]þ 705.29. Found: 705.37. Anal. Calcd for C37H46O12

(682.75): C, 65.09; H, 6.79. Found: C, 65.33; H, 6.87.

4.3. Methyl (2-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-copyranoside (7)

To a solution of 6 (2.000 g, 2.93 mmol) in dry pyridine (10 mL),tert-butyldimethylsilyl chloride (883 mg, 5.96 mmol) was added.

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927 2923

The mixture was stirred for 24 h at room temperature. After com-plete disappearance of the starting material the mixture was con-centrated. The residue was dissolved in EtOAc (250 mL), washedwith 1MHCl (2�20mL), water (20mL), satd aq NaHCO3 (2�20mL)and water (2�20 mL), dried and concentrated. The crude productwas purified by column chromatography on silica gel (6:4 n-hex-ane/EtOAc) to give 7 (2.250 g, 96%) as a colourless syrup; [a]D25 þ4.0(c 0.33, CHCl3); Rf 0.51 (6:4 n-hexane/EtOAc); IR nmax (KBr): 3585,3480, 3088, 3063, 3030, 2929, 2895, 2857, 1739, 1605, 1496, 1471,1455, 1370, 1248, 1098, 1050, 912, 836, 777, 739, 698, 606, 548, 466,419 cm�1; 1H NMR (CDCl3, 360 MHz): d¼7.54e7.41 (m, 15H, arom),5.16e4.67 (m, 9H, 3�CH2Ph, H-1, H-10, H-20), 4.36e4.31 (m, 1H),4.12e4.01 (m, 2H), 3.98e3.91 (m, 2H), 3.85e3.72 (m, 4H), 3.16 (s,3H, OCH3), 3.58e3.54 (m, 2H), 3.52 (s, 3H, OCH3), 3.47e3.43 (m,1H),2.15 (s, 3H, AcCH3), 1.04 (s, 9H, 3�t-Bu-CH3), 0.19, 0.16 (2�s, 6H,2�CH3) ppm; 13C NMR (CDCl3, 90 MHz): d¼169.4 (CO), 138.8, 137.8,137.7 (3C, 3�Cq arom), 127.9e126.9 (15C, arom), 97.7, 97.5 (C-1, C-10), 80.6, 79.9, 77.7, 73.4, 69.8, 67.9, 67.3, 65.7 (8C, skeleton carbons),75.1, 73.0, 72.9 (3C, 3�CH2Ph), 68.3 (C-6), 63.8 (C-60), 57.7 (C-30-OCH3), 54.8 (C-1-OCH3), 25.5 (3C, 3�t-Bu-CH3), 20.7 (AcCH3), 17.9(Cq, t-Bu), �5.8 (2C, 2�CH3) ppm; MALDI-TOF (positive ion): m/zcalcd for [MþNa]þ 819.37. Found: 819.20. Anal. Calcd forC43H60O12Si (796.39): C, 64.80; H, 7.59. Found: C, 64.95; H, 7.68.

4.4. Phenyl 2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-1-thio-b-D-glucopyranoside (9)

To a solution of compound 816 (10.92 g, 18.43 mmol) in dry DMF(65 mL) NaH (60% dispersion in oil, 1.180 g, 29.49 mmol) was addedin portions at 0 �C. After stirring for 30 min at 0 �C under Ar, benzylbromide (2.630 mL, 22.12 mmol) was added. When completeconversion of the starting material was observed by TLC analysis(3 h at 0 �C), MeOH (2 mL) was added. The reaction mixture wasstirred for 5 min and the solvents were evaporated. The crudeproduct was purified by crystallization from EtOAc/n-hexane (1:4,60 mL) to give 9 (11.68 g, 93%) as white needles; mp: 92e94 �C;[a]D25 �3.1 (c 0.23, CHCl3); Rf 0.48 (7:3 n-hexane/EtOAc); IR nmax(KBr): 3436, 3059, 3030, 2949, 2900, 2870, 1603, 1586, 1509, 1497,1482,1469,1454,1441,1398,1376,1356,1289,1270,1211,1175,1135,1093, 1064, 1029, 1009, 987, 957, 854, 816, 755, 733, 697, 641,477 cm�1; 1H NMR (CDCl3, 360 MHz) d¼7.82e7.70 (m, 3H),7.64e7.55 (m, 3H), 7.48e7.19 (m, 21H), 5.02e4.84 (m, 4H),4.78e4.65 (m, 3H), 4.50 (d, 1H, 12.0 Hz), 4.44 (d, 1H, 12.0 Hz),3.85e3.67 (m, 4H), 3.58e3.44 (m, 2H); 13C NMR (CDCl3, 90 MHz)d¼138.6, 138.4, 138.2, 135.6, 133.9, 133.3, 133.1, 132.0, 129.0, 128.5,128.3, 128.0, 127.8, 127.6, 127.5, 126.7, 126.2, 126.0 (34C, arom), 87.6,86.9, 81.0, 79.2, 77.9 (5C, C-1eC-5), 75.9, 75.5, 75.2, 73.5 (4C,4�CH2Ar), 69.1 (C-6). Anal. Calcd for C44H42O5S (682.87): C, 77.39;H, 6.20; S, 4.70. Found: C, 77.17; H, 6.27; S, 4.91.

4.5. Methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-a-D-glucopyranosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldime-thylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (10), methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-a-D-glucopyranosyl)-(1/4)-(2-O-acetyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-ben-zyl-a-D-glucopyranoside (11), tert-butyldimethylsilyl 2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-a,b-D-glucopyranoside (12)and methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-a-D-glucopyranosyl)-(1/4)-[2-O-acetyl-6-O-(2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-a,b-D-glucopyranosyl)-3-O-methyl-a-L-idopyranosyl]-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside(13)

4.5.1. Method A. To a solution of disaccharide acceptor 7 (2.200 g,2.76mmol) andmonosaccharide donor 9 (2.820 g, 4.14mmol) in dry

CH2Cl2 (72mL), 4�Amolecular sieves (2.00 g)were added. The stirredmixture was cooled to �40 �C under argon. After 30 min at thistemperature, amixture of NIS (1.397 g, 6.21mmol) and TfOH (162 mL,1.86mmol) dissolved in THF (3.6mL) was added. After 2 h stirring at�10 �C, Et3N (500 mL) was added. The reaction mixture was dilutedwith CH2Cl2 (400mL) andfiltered through a pad of Celite. The filtratewas washed successively with 10% aq Na2S2O3 (2�60 mL), H2O(60 mL), satd aq NaHCO3 (60 mL) and H2O (2�60 mL), dried andconcentrated. The crude product was purified by silica gel chroma-tography (9:1 to 7:3n-hexane/EtOAc) to give compounds10 (325mg,9%), 11 (1.831 g, 49%), 12 (572 mg, 15%) and 13 (881 mg, 24%).

4.5.2. Method B. To a solution of disaccharide 7 (210 mg,0.273 mmol) and monosaccharide 9 (279 mg, 0.41 mmol) in dryCH2Cl2 (7 mL), 4 �A molecular sieves (0.50 g) and sym-collidine(6.500 mL, 0.05 mmol) were added. The stirred mixture was cooledto �40 �C under argon. After 30 min at this temperature, NIS(138 mg, 0.61 mmol) dissolved in THF (360 mL) and AgOTf (25 mg,0.10 mmol) dissolved in toluene (300 mL) were added. After 3 hstirring at 10 �C, Et3N (50 mL) was added. The reaction mixture wasdiluted with CH2Cl2 (250 mL) and filtered through a pad of Celite.The filtrate was washed successively with 10% aq Na2S2O3(2�50 mL), H2O (50 mL), satd aq NaHCO3 (50 mL) and H2O(2�50mL), dried and concentrated. The crude product was purifiedby silica gel chromatography (7:3 n-hexane/EtOAc) to give 10(265 mg, 71%) as the only isolated product.

4.5.3. Compound 10. Colourless syrup; [a]D25 þ15.6 (c 0.09, CHCl3);Rf 0.40 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3087, 3061, 3029, 2927,2857,1736,1603,1585,1496,1454,1363,1235,1094,1050,1027, 910,836, 817, 777, 736, 697, 606, 553, 475 cm�1; 1H NMR (CDCl3,360 MHz): d¼7.88e7.21 (m, 37H, arom), 5.21e4.48 (m, 18H,6�CH2Ph, CH2NAP, H-1, H-10, H-100, H-20), 4.18e3.79 (m, 14H),3.69e3.66 (m, 2H), 3.59e3.55 (m, 1H), 3.44 (s, 3H, OCH3), 3.41 (s,3H, OCH3), 2.04 (s, 3H, AcCH3), 1.01 (s, 9H, 3�t-Bu-CH3), 0.15, 0.13(2�s, 6H, 2�CH3) ppm; 13C NMR (CDCl3, 90 MHz): d¼169.6 (CO),139.1, 138.4, 138.2, 138.1, 138.0, 137.6, 135.7, 133.0, 132.6 (9C, 9�Cqarom), 128.1e125.5 (37C, arom), 98.4, 98.0, 97.8 (C-1, C-10, C-100),81.7, 80.0, 79.6, 79.4, 78.4, 77.3, 76.2, 74.3, 71.3, 71.2, 70.8, 70.0 (12C,skeleton carbons), 75.2, 75.0, 74.8, 74.6, 73.3, 73.2, 72.9 (7C,6�CH2Ph, CH2NAP), 68.8, 68.0 (C-6, C-600), 62.3 (C-60), 58.7 (C-30-OCH3), 54.9 (C-1-OCH3), 25.8 (3C, 3�t-Bu-CH3), 20.8 (AcCH3), 17.9(Cq, t-Bu), �5.4, �5.6 (2C, 2�CH3) ppm; MALDI-TOF (positive ion):m/z calcd for [MþNa]þ 1391.63. Found: 1391.72. Anal. Calcd forC81H96O17Si (1368.64): C, 71.03; H, 7.06. Found: C, 71.20; H, 7.12.

4.5.4. Compound 11. Colourless syrup; [a]D25þ17.7 (c 0.12, CHCl3); Rf0.16 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3466, 3087, 3061, 3029,2928, 2867, 1733, 1630, 1604, 1496, 1454, 1368, 1239, 1157, 1098,1050, 1027, 908, 855, 818, 738, 698, 474 cm�1; 1H NMR (CDCl3,360 MHz): d¼7.77e7.27 (m, 37H, arom), 5.07e4.38 (m, 18H,6�CH2Ph, CH2NAP, H-1, H-10, H-100, H-20), 4.25e4.21 (m, 1H),4.00e3.58 (m, 17H), 3.39 (s, 3H, OCH3), 3.32 (s, 3H, OCH3), 1.93 (s,3H, AcCH3) ppm; 13C NMR (CDCl3, 90 MHz): d¼169.6 (CO), 138.3,138.2, 137.7, 137.5, 137.3, 135.4, 132.8, 132.5 (9C, 9�Cq arom),128.0e125.3 (37C, arom), 98.2, 97.6, 96.8 (C-1, C-10, C-100), 81.5, 79.9,79.1, 77.4, 76.5, 73.2, 70.9, 69.8, 68.5, 67.5 (12C, skeleton carbons),75.3, 75.0, 74.5, 73.1, 72.9 (7C, 6�CH2Ph, CH2NAP), 68.1, 68.0 (C-6, C-600), 60.9 (C-60), 57.7 (C-30-OCH3), 54.7 (C-1-OCH3), 20.6(AcCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ

1277.54. Found: 1277.76. Anal. Calcd for C75H82O17 (1254.56): C,71.75; H, 6.58. Found: C, 71.83; H, 6.63.

4.5.5. Compound 12. Colourless syrup (a/b ratio¼3:1); [a]D25 þ6.1 (c0.44, CHCl3); Rf 0.84 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3058,3030, 2926, 2856, 1578, 1476, 1438, 1361, 1252, 1156, 1072, 1023,

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e29272924

999, 837, 817, 780, 737, 687, 471 cm�1; 1H NMR (CDCl3, 360 MHz):d¼7.74e7.09 (m, 30H, arom), 5.27 (d, 1H, J 3.4 Hz, H-1-a), 5.00e4.37(m, 12H, 6�CH2Ph, 2�CH2NAP, H-1-b), 4.07e3.45 (m, 8H), 0.96 (s,3H, 3�t-Bu-CH3), 0.93 (s, 9H, 3�t-Bu-CH3), 0.20, 0.17 (2�s, 2H,2�CH3) 0.14, 0.13 (2�s, 6H, 2�CH3) ppm; 13C NMR (CDCl3, 90MHz):d¼138.8, 138.6, 138.4, 138.3, 138.1, 137.8, 136.8, 135.7, 133.1, 132.8(14C, 14�Cq arom), 128.8e125.6 (44C, arom), 98.1 (C-1-b), 91.7 (C-1-a), 84.6, 83.8, 81.6, 80.9, 77.7, 75.0, 70.2 (8C, skeleton carbons),75.4, 75.3, 75.1, 74.7, 74.6, 73.3, 73.1, 72.7 (8C, 6�CH2Ph,2�CH2NAP), 68.9, 68.5 (2�C-6), 25.7, 25.6 (6C, 6�t-Bu-CH3), 18.0,17.9 (2C, 2�Cq, t-Bu), �4.1, �4.6, �5.1, �5.4 (4C, 4�CH3) ppm;MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 727.34. Found:727.24. Anal. Calcd for C44H52O6Si (704.35): C, 74.96; H, 7.43. Found:C, 75.06; H, 7.57.

4.5.6. Compound 13. Colourless syrup (a/b ratio¼1:1); [a]D25 þ14.6(c 0.37, CHCl3); Rf 0.33 (7:3 n-hexane/EtOAc); IR nmax (KBr): 3167,3087, 3061, 3029, 2924, 2863, 1952, 1869, 1809, 1736, 1603, 1585,1496, 1454, 1365, 1327, 1235, 1162, 1098, 1026, 1001, 911, 856, 818,736, 698, 605, 476 cm�1; 1H NMR (CDCl3, 360 MHz): d¼7.79e7.18(m, 118H, arom), 5.14e4.24 (m, 54H, 18�CH2Ph, 4�CH2NAP, 2�H-1,2�H-10, 2�H-100, 2�H-20, H-1000-a, H-1000-b), 4.11e4.28 (m, 58H), 2.01,1.96 (2�s, 6H, 2�AcCH3) ppm; 13C NMR (CDCl3, 90 MHz): d¼169.9,169.8 (2C, 2�CO), 139.3, 139.2, 138.7, 138.6, 138.5, 138.1, 138.0, 137.9,137.7, 135.9, 135.8, 135.7, 133.1, 132.8 (30C, 30�Cq arom),128.2e125.7 (C, arom), 103.4, 99.1, 98.9, 98.2, 98.0, 97.8, 97.4, 97.3(2�C-1, 2�C-10, 2�C-100, C-1000-a, C-1000-b), 82.2, 81.8, 80.2, 80.0, 79.7,79.4, 79.3, 77.7, 77.5, 77.3, 76.6, 71.4, 70.6, 70.1 (32C, skeleton car-bons), 75.4, 75.3, 75.1, 74.9, 74.6, 73.3, 73.2, 73.0, 72.0 (22C,18�CH2Ph, 4�CH2NAP), 68.5, 68.4, 68.2, 66.9, 66.4 (8C, 8�C-6),58.7, 58.2 (2C, 2�C-30-OCH3), 55.0 (2C, 2�C-1-OCH3), 25.9, 25.6 (2C,2�AcCH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ

1849.80. Found: 1850.03. Anal. Calcd for C113H118O22 (1826.81): C,74.24; H, 6.51. Found: C, 74.29; H, 6.57.

4.6. Methyl (2-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-copyranoside (14)

Compound 6 (730 mg, 1.07 mmol) was silylated with tert-butyldiphenylsilyl chloride (556 mL, 2.14 mmol) as described for thesynthesis of 7. The crude product was purified by column chro-matography on silica gel (6:4 n-hexane/EtOAc) to give 14 (895 mg,91%) as a colourless syrup; [a]D25 þ4.8 (c 0.05, CHCl3); Rf 0.47 (6:4 n-hexane/EtOAc); IR nmax (KBr): 3481, 3030, 2931, 2892, 2857, 1738,1472, 1428, 1232, 1048, 822, 737, 699, 613, 504, 489 cm�1; 1H NMR(CDCl3, 360 MHz): d¼7.69e7.08 (m, 25H, arom), 4.99e4.49 (m, 9H,3�CH2Ph, H-1, H-10, H-20), 4.25e4.32 (m, 1H), 3.92e3.63 (m, 7H),3.48e3.41 (m, 3H), 3.45 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.31e3.27(m, 1H), 1.98 (s, 3H, AcCH3), 1.02 (s, 9H, 3�t-Bu-CH3) ppm; 13C NMR(CDCl3, 90 MHz): d¼169.6 (CO), 138.7, 138.0, 137.8, 133.0, 132.6 (5C,5�Cq arom), 135.7e127.0 (25C, arom), 98.0, 97.6 (C-1, C-10), 80.1,80.0, 77.9, 73.3, 69.9, 68.0, 67.5, 65.9 (8C, skeleton carbons), 75.3,73.2 (3C, 3�CH2Ph), 68.9 (C-6), 64.6 (C-60), 58.0 (C-30-OCH3), 55.0(C-1-OCH3), 26.6 (3C, 3�t-Bu-CH3), 20.9 (AcCH3), 19.0 (Cq, t-Bu) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 943.41.Found: 943.45. Anal. Calcd for C53H64O12Si (920.42): C, 69.11; H,7.00. Found: C, 69.21; H, 7.10.

4.7. Methyl (2,3,6-tri-O-benzyl-4-O-(2-naphthyl)methyl-a-D-glucopyranosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldiphe-nylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-ben-zyl-a-D-glucopyranoside (15)

To a solution of disaccharide acceptor 14 (880 mg, 0.96 mmol)and thiophenyl-glycoside donor 9 (978 mg, 1.43 mmol) in dry

CH2Cl2 (22 mL), 4 �A molecular sieves (0.500 g) were added. Thestirred mixture was cooled to �40 �C under argon. After 30 min atthis temperature, NIS (483 mg, 2.151 mmol) dissolved in THF(1.00 mL) and AgOTf (88 mg, 0.34 mmol) dissolved in toluene(1.00mL) were added. After 2 h stirring at�10 �C, Et3N (100 mL) wasadded. The reaction mixture was diluted with CH2Cl2 (250 mL) andfiltered through a pad of Celite. The filtrate was washed succes-sively with 10% aq Na2S2O3 (2�50 mL), H2O (50 mL), satd aqNaHCO3 (50 mL) and H2O (2�50 mL), dried and concentrated. Thecrude product was purified by silica gel chromatography (7:3 n-hexane/EtOAc) to give 15 (1.10 g, 77%) as a colourless syrup; [a]D25

þ4.9 (c 0.12, CHCl3); Rf 0.35 (7:3 n-hexane/EtOAc); IR nmax (KBr):3479, 3063, 3029, 2931, 2856, 1736, 1496, 1454, 1428, 1363, 1236,1159, 1110, 1027, 910, 855, 820, 748, 699, 614, 505, 476 cm�1; 1HNMR (CDCl3, 360 MHz): d¼7.78e7.15 (m, 47H, arom), 5.15e4.49 (m,18H, 6�CH2Ph, CH2NAP, H-1, H-10, H-100, H-20), 4.31e4.22 (m, 2H),3.97e3.47 (m,14H), 3.36 (s, 3H, OCH3), 3.35 (s, 3H, OCH3), 3.20e3.17(m, 1H), 1.94 (s, 3H, AcCH3), 1.07 (s, 9H, 3�t-Bu-CH3) ppm; 13C NMR(CDCl3, 90 MHz): d¼169.5 (CO), 139.1, 138.6, 138.5, 138.0, 137.9,137.8, 137.5, 135.6, 133.0, 132.9, 132.6 (11C, 11�Cq arom),135.3e125.5 (47C, arom), 98.8, 97.8, 97.7 (C-1, C-10, C-100), 81.6, 81.4,80.2, 79.3, 77.8, 75.7, 74.7, 70.9, 70.5, 70.3, 69.9, 69.8 (12C, skeletoncarbons), 75.1, 74.5, 73.2, 73.0, 72.9, 72.7 (7C, 6�CH2Ph, CH2NAP),68.8, 67.5 (C-6, C-600), 63.1 (C-60), 58.5 (C-30-OCH3), 54.8 (C-1-OCH3),26.7 (3C, 3�t-Bu-CH3), 20.7 (AcCH3), 18.8 (Cq, t-Bu) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 1515.66. Found:1515.61. Anal. Calcd for C91H100O17Si (1492.67): C, 73.17; H, 6.75.Found: C, 73.29; H, 7.02.

4.8. Methyl (2,3,6-tri-O-benzyl-a-D-glucopyranosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-methyl-a-L-ido-pyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (16)

To a vigorously stirred solution of 10 (300 mg, 0.22 mmol) inCH2Cl2 (3.5 mL) and H2O (0.50 mL), DDQ (75 mg, 0.33 mmol) wasadded. After 30 min the mixture was diluted with CH2Cl2 (150 mL)and extracted with satd aq NaHCO3 (2�20 mL) and H2O (2�20 mL),dried and concentrated. The crude product was purified by silica gelchromatography (9:1 CH2Cl2/acetone) to give 16 (128 mg, 47%) asa colourless syrup; [a]D25 þ15.8 (c 0.09, CHCl3); Rf 0.63 (9:1 CH2Cl2/acetone); IR nmax (KBr): 3481, 3088, 3063, 3030, 2927, 2856, 2348,2310, 1944, 1747, 1626, 1496, 1455, 1428, 1362, 1235, 1116, 1026, 904,836, 778, 736, 697, 606, 505, 421 cm�1; 1H NMR (CDCl3, 360 MHz):d¼7.41e7.18 (m, 30H, arom), 5.11e4.49 (m,16H, 6�CH2Ph, H-1, H-10,H-100, H-20), 4.03e4.02 (m, 1H), 3.88e3.67 (m, 13H), 3.58e3.45 (m,3H), 3.36 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 2.54 (s, 1H, OH), 1.94 (s,3H, AcCH3), 0.89 (s, 9H, 3�t-Bu-CH3), 0.05, 0.02 (2�s, 6H,2�CH3) ppm; 13C NMR (CDCl3, 90 MHz): d¼169.6 (CO), 139.2, 138.6,138.2, 138.1, 138.0, 137.7 (6C, 6�Cq arom), 128.4e127.0 (30C, arom),98.5, 98.2, 97.9 (C-1, C-10, C-100), 81.0, 80.1, 79.4, 79.3, 78.8, 76.5, 74.8,71.8, 71.2, 71.0, 70.8, 70.2 (12C, skeleton carbons), 75.2, 75.1, 73.6,73.4, 73.3, 72.7 (6C, 6�CH2Ph), 69.4, 68.9 (C-6, C-600), 62.5 (C-60),59.0 (C-30-OCH3), 55.0 (C-1-OCH3), 25.8 (3C, 3�t-Bu-CH3), 20.8(AcCH3), 18.0 (Cq, t-Bu), �5.4, �5.6 (2C, 2�CH3) ppm; MALDI-TOF(positive ion): m/z calcd for [MþNa]þ 1251.57. Found: 1251.62.Anal. Calcd for C70H88O17Si (1229.54): C, 68.38; H, 7.21. Found: C,68.33; H, 7.31.

4.9. Methyl (2,3,6-tri-O-benzyl-a-D-glucopyranosyl)-(1/4)-(2-O-acetyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (17)

Compound 11 (1.820 g, 1.45 mmol) was deprotected in ananalogous manner to that described for the synthesis of compound16. The crude product was purified by silica gel chromatography(1:1 n-hexane/acetone) to give 17 (1.110 g, 69%) as a colourless

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927 2925

syrup; [a]D25 þ2.1 (c 0.08, CHCl3); Rf 0.42 (1:1 n-hexane/acetone); IRnmax (KBr): 3445, 3063, 3030, 2928, 1734, 1633, 1496, 1454, 1370,1238, 1098, 1051, 1027, 912, 739, 698 cm�1; 1H NMR (CDCl3,360 MHz): d¼7.38e7.21 (m, 30H, arom), 4.99e4.49 (m, 16H,6�CH2Ph, H-1, H-10, H-100, H-20), 4.16e4.06 (m, 2H), 3.92e3.88 (m,2H), 3.79e3.25 (m, 14H), 3.37 (s, 3H, OCH3), 3.33 (s, 3H, OCH3), 2.58(s, 1H, OH), 1.91 (s, 3H, AcCH3) ppm; 13C NMR (CDCl3, 90 MHz):d¼169.6 (CO), 138.4, 138.3, 137.8, 137.7, 137.6, 135.5 (6C, 6�Cq arom),128.2e127.5 (30C, arom), 97.8, 97.7, 96.9 (C-1, C-10, C-100), 80.0, 79.9,78.8, 76.7, 72.9, 72.7, 70.9, 70.8, 68.8, 67.8, 67.7 (12C, skeleton car-bons), 75.6, 75.0, 73.4, 73.2, 73.0 (6C, 6�CH2Ph), 69.1 (2C, C-6, C-600),60.9 (C-60), 58.0 (C-30-OCH3), 54.9 (C-1-OCH3), 20.8 (AcCH3) ppm;MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 1137.48. Found:1137.71. Anal. Calcd for C64H74O17 (1114.46): C, 68.92; H, 6.69.Found: C, 69.11; H, 6.75.

4.10. Methyl (2,3,6-tri-O-benzyl-a-D-glucopyranosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-methyl-a-L-ido-pyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (18)

4.10.1. Method A. Compound 15 (980 mg, 0.66 mmol) was depro-tected in an analogousmanner to that described for the synthesis ofcompound 16. The crude product was purified by silica gel chro-matography (7:1 n-hexane/acetone) to give 18 (654 mg, 74%) asa colourless syrup.

4.10.2. Method B. Compound 17 (1.100 g, 0.987 mmol) was tert-butyldiphenylsilylated with tert-butyldiphenylsilyl chloride(514 mL, 1.974 mmol) in an analogous manner to that described forthe synthesis of compound 14. The crude product was purified bysilica gel chromatography (6:4 n-hexane/EtOAc) to give 18 (1.092 g,82%) as a colourless syrup; [a]D25 þ35.5 (c 0.10, CH2Cl2); Rf 0.56 (6:4n-hexane/EtOAc); IR nmax (KBr): 3479, 3087, 3064, 3030, 2930,2856, 1735, 1605, 1496, 1454, 1428, 1365, 1236, 1111, 1046, 1027, 910,822, 738, 698, 613, 505 cm�1; 1H NMR (CDCl3, 360 MHz):d¼7.71e7.14 (m, 40H, arom), 5.12e4.34 (m, 16H, 6�CH2Ph, H-1, H-10, H-100, H-20), 4.21e4.17 (m, 1H), 3.93e3.42 (m, 15H), 3.37 (s, 3H,OCH3), 3.33 (s, 3H, OCH3), 3.28e3.25 (m, 1H), 2.38 (s, 1H, OH), 1.94(s, 3H, AcCH3), 1.05 (s, 9H, 3�t-Bu-CH3) ppm; 13C NMR (CDCl3,90 MHz): d¼169.6 (CO), 139.1, 138.6, 138.2, 138.1, 137.9, 137.7, 133.0,132.7 (8C, 8�Cq arom), 135.5e126.9 (40C, arom), 98.7, 98.0, 97.9 (C-1, C-10, C-100), 81.2, 80.4, 79.4, 79.1, 78.3, 76.3, 74.7, 71.2, 71.0, 70.8,70.7, 70.1 (12C, skeleton carbons), 75.3, 74.9, 73.4, 73.3, 73.1, 72.9(6C, 6�CH2Ph), 68.9 (2C, C-6, C-600), 63.1 (C-60), 58.8 (C-30-OCH3),55.0 (C-1-OCH3), 26.8 (3C, 3�t-Bu-CH3), 20.9 (AcCH3), 19.0 (Cq, t-Bu) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ

1375.60. Found: 1375.74. Anal. Calcd for C80H92O17Si (1352.61): C,70.98; H, 6.85. Found: C, 71.14; H, 7.03.

4.11. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-b-D-glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyr-anosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldimethylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-copyranoside (20)

To a solution of trisaccharide acceptor 16 (128 mg, 0.10 mmol),and disaccharide donor 1910 (123 mg, 0.16 mmol) in dry CH2Cl2(5 mL), 4 �A molecular sieves (0.500 g) were added. The stirredmixture was cooled to �40 �C under argon. After 30 min at thistemperature, NIS (52 mg, 0.23 mmol) dissolved in THF (150 mL) andAgOTf (10 mg, 0.04 mmol) dissolved in toluene (150 mL) wereadded. After 3 h stirring at þ5 �C, Et3N (50 mL) was added. Thereaction mixture was diluted with CH2Cl2 (150 mL), and filteredthrough a pad of Celite. The filtrate was washed successively with10% aq Na2S2O3 (2�25 mL), H2O (25 mL), satd aq NaHCO3 (25 mL),

H2O (2�50 mL), dried and concentrated. The crude product waspurified by silica gel chromatography (7:3 n-hexane/acetone) togive 20 (116 mg, 58%) as a colourless syrup; [a]D25 þ32.6 (c 0.10,CHCl3); Rf 0.35 (7:3 n-hexane/acetone); IR nmax (KBr): 3459, 3062,3029, 2928, 2857, 1753, 1734, 1454, 1364, 1240, 1219, 1100, 1049,836, 747, 698 cm�1; 1H NMR (CDCl3, 360 MHz): d¼7.80e7.12 (m,42H, arom), 5.14e4.26 (m, 24H, 7�CH2Ph, CH2NAP, 5�H-1, H-20, H-2000, H-3000), 4.08e3.68 (m, 19H), 3.55e3.04 (m, 8H), 3.54, 3.41, 3.35,3.21 (4�s, 15H, 5�OCH3), 2.02, 1.90, 1.87 (3�s, 9H, 3�AcCH3), 0.87(s, 9H, 3�t-Bu-CH3), 0.00 (s, 6H, 2�CH3) ppm; 13C NMR (CDCl3,90 MHz): d¼169.8, 169.3 (3C, 3�CO), 139.3, 138.2, 138.1, 137.9, 137.4,136.0, 133.2, 132.7 (10C, 10�Cq arom), 132.3e125.5 (42C, arom),99.7, 99.0, 97.9, 97.7 (5�C-1), 83.1, 81.7, 80.2, 79.8, 79.6, 79.2, 77.7,75.9, 75.2, 75.0, 74.8, 74.6, 72.7, 71.2, 71.1, 70.2, 70.1, 69.8 (20C,skeleton carbons), 75.1, 74.9, 73.7, 73.5, 73.4, 73.2 (8C, 7�CH2Ph,CH2NAP), 69.0, 68.7, 68.3, 67.5 (4C, 4�C-6), 62.3 (C-60), 60.6, 60.3,59.1, 58.5 (4C, 4�OCH3), 55.0 (C-1-OCH3), 25.9 (3C, 3�t-Bu-CH3),20.9, 20.6 (3C, 3�AcCH3), 18.0 (Cq, t-Bu), �5.4, �5.5 (2C,2�CH3) ppm; MALDI-TOF (positive ion): m/z calcd for [MþNa]þ

1931.85. Found: 1932.27. Anal. Calcd for C107H132O29Si (1908.86): C,67.28; H, 6.96. Found: C, 67.37; H, 7.12.

4.12. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(2,3-di-O-acetyl-6-O-(2-naphthyl)methyl-b-D-glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyr-anosyl)-(1/4)-(2-O-acetyl-6-O-tert-butyldiphenylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-copyranoside (21)

Compound 18 (1.080 g, 0.80 mmol) was glycosylated with 1910

(948 mg, 1.20 mmol) in an analogous manner to that describedfor the synthesis of compound 20. The crude product was purifiedby silica gel chromatography (1:1 n-hexane/EtOAc) to give 21(1.238 g, 76%) as a colourless syrup; [a]D25 þ34.8 (c 0.09, CHCl3); Rf0.54 (1:1 n-hexane/EtOAc); IR nmax (KBr): 3445, 3062, 3029, 2931,2858,1754,1731,1496,1472,1454,1428,1365,1295,1241,1157,1143,1103, 1028, 903, 820, 740, 699, 613, 502 cm�1; 1H NMR (CDCl3,360 MHz): d¼7.79e7.12 (m, 52H, arom), 5.08e4.24 (m, 24H,7�CH2Ph, CH2NAP, 5�H-1, H-20, H-2000, H-3000), 4.12e3.62 (m, 15H),3.47e3.04 (m, 12H), 3.59, 3.41, 3.39, 3.35, 3.23 (5�s, 15H, 5�OCH3),2.00, 1.90, 1.73 (3�s, 9H, 3�AcCH3), 1.04 (s, 9H, 3�t-Bu-CH3) ppm;13C NMR (CDCl3, 90 MHz): d¼169.8, 169.7, 169.2 (3C, 3�CO), 139.2,139.1, 138.1, 138.0, 137.9, 137.8, 137.4, 135.9, 133.1, 133.0, 132.7, 132.6(12C, 12�Cq arom), 135.4e125.4 (52C, arom), 99.4, 99.1, 97.8, 97.6(5C, 5�C-1), 83.0, 81.6, 80.3, 79.8, 79.5, 79.2, 79.1, 77.2, 76.2, 75.6,75.0, 74.9, 74.3, 72.5, 71.0, 69.9, 69.6, 69.5 (20C, skeleton carbons),75.2, 74.7, 73.6, 73.5, 73.2, 73.1 (8C, 7�CH2Ph, CH2NAP), 69.0, 68.6,68.2, 67.3 (4C, 4�C-6), 63.0 (C-60), 60.4, 60.1, 59.0, 58.2 (4C,4�OCH3), 54.9 (C-1-OCH3), 26.7 (3C, 3�t-Bu-CH3), 20.8, 20.3 (3C,3�AcCH3), 18.9 (Cq, t-Bu) ppm; MALDI-TOF (positive ion):m/z calcdfor [MþNa]þ 2055.88. Found: 2056.30. Anal. Calcd for C117H136O29Si(2032.89): C, 69.07; H, 6.74. Found: C, 69.19; H, 6.83.

4.13. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(6-O-(2-naphthyl)methyl-b-D-glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyranosyl)-(1/4)-(6-O-tert-butyldiphenylsilyl-3-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (22)

To a solution of 21 (1.220 g, 0.60 mmol) in MeOH (20 mL)a catalytic amount of NaOMe (40 mg, 0.74 mmol) was added. After24 h stirring, themixturewas neutralizedwith Amberlite IR-120 Hþ

ion-exchange resin, filtered and concentrated. The crude productwas purified by silica gel chromatography (1:1 n-hexane/EtOAc) togive 22 (899 mg, 79%) as a colourless syrup; [a]D25 þ35.3 (c 0.09,CHCl3); Rf 0.44 (1:1 n-hexane/EtOAc); IR nmax (KBr): 3437, 3062,

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e29272926

3029, 2930, 2858, 1632, 1605, 1496, 1454, 1428, 1362, 1098, 1048,913, 856, 821, 739, 699, 612, 505, 476 cm�1; 1H NMR (CDCl3,360 MHz): d¼7.79e7.18 (m, 52H, arom), 5.13e4.31 (m, 21H,7�CH2Ph, CH2NAP, 5�H-1), 3.98e3.68 (m, 10H), 3.63e3.30 (m,15H), 3.61, 3.58, 3.43, 3.37, 3.26 (5�s, 15H, 5�OCH3), 3.21e3.14 (m,7H), 2.61 (s, 1H, OH), 1.03 (s, 9H, 3�t-Bu-CH3) ppm; 13C NMR (CDCl3,90 MHz): d¼139.1, 138.2, 137.9, 137.7, 137.5, 137.4, 136.1, 133.4, 133.0,132.8, 132.6 (12C, 12�Cq arom), 135.5e125.4 (52C, arom), 102.4,100.4, 100.3, 97.9, 95.8 (5C, 5�C-1), 83.8, 82.6, 81.9, 80.6, 79.8, 79.2,77.9, 75.8, 75.7, 74.6, 74.2, 73.5, 71.1, 70.7, 69.9, 67.3, 67.0 (20C,skeleton carbons), 75.0, 74.9, 73.9, 73.2, 73.1 (8C, 7�CH2Ph,CH2NAP), 69.1, 68.8, 68.2, 67.5 (4C, 4�C-6), 63.7 (C-60), 60.5, 60.2,60.0, 57.7 (4C, 4�OCH3), 54.9 (C-1-OCH3), 26.8 (3C, 3�t-Bu-CH3),18.9 (Cq, t-Bu) ppm; MALDI-TOF (positive ion): m/z calcd for[MþNa]þ 1929.85. Found: 1929.96. Anal. Calcd for C111H130O26Si(1906.86): C, 69.86; H, 6.87. Found: C, 69.99; H, 6.93.

4.14. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(2,3-di-O-methyl-6-O-(2-naphthyl)methyl-b-D-glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyr-anosyl)-(1/4)-(6-O-tert-butyldiphenylsilyl-2,3-di-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyrano-side (23)

To a solution of pentasaccharide triol 22 (885 mg, 0.46 mmol) indry DMF (17 mL) NaH (60% dispersion in oil, 67mg, 1.66 mmol) wasadded at 0 �C. After stirring for 30min at 0 �C under Ar, MeI (108 mL,1.73 mmol) was added. When complete disappearance of thestarting material was observed by TLC analysis (3 h at 0 �C), MeOH(2 mL) was added. The reaction mixture was stirred for 5 min andthe solvents were evaporated. The crude product was purified bycolumn chromatography (7:3 n-hexane/acetone) to give 23(771 mg, 85%) as a colourless syrup. [a]D25 þ45.2 (c 0.08, CHCl3); Rf0.43 (7:3 n-hexane/acetone); IR nmax (KBr): 3465, 3062, 3029, 2931,2858, 1636, 1496, 1454, 1428, 1363, 1103, 1070, 1026, 911, 856, 819,735, 697, 614, 504 cm�1; 1H NMR (CDCl3, 360 MHz): d¼7.78e7.11(m, 52H, arom), 5.59 (d,1H, J 3.5 Hz), 5.29 (d,1H, J 3.7 Hz), 5.17e4.29(m, 19H, 7�CH2Ph, CH2NAP, 3�H-1), 4.12e3.68 (m, 16H), 3.63e3.15(m, 12H), 3.60, 3.57, 3.53, 3.49, 3.44, 3.41, 3.37, 3.26 (8�s, 24H,8�OCH3), 3.04e2.96 (m, 2H), 1.04 (s, 9H, 3�t-Bu-CH3) ppm; 13CNMR (CDCl3, 90 MHz): d¼139.6, 139.2, 138.2, 137.8, 137.6, 136.2,133.0, 132.7, 132.6, 132.3 (12C, 12�Cq arom), 135.4e125.3 (52C,arom), 102.5, 100.9, 98.2, 97.7, 96.0 (5C, 5�C-1), 86.4, 84.6, 84.5,83.2, 82.0, 81.6, 80.3, 80.1, 79.1, 79.0, 78.7, 78.5, 76.7, 75.3, 74.5, 73.3,72.3, 71.1, 70.5, 70.4 (20C, skeleton carbons), 75.2, 74.6, 73.2, 73.1,72.9, 72.8 (8C, 7�CH2Ph, CH2NAP), 69.2, 69.0, 67.9, 67.3 (4C, 4�C-6),63.0 (C-60), 60.5, 60.1, 60.0, 59.5, 59.2 (7C, 7�OCH3), 54.9 (C-1-OCH3), 26.7 (3C, 3�t-Bu-CH3), 18.8 (Cq, t-Bu) ppm; MALDI-TOF(positive ion): m/z calcd for [MþNa]þ 1971.90. Found: 1972.03.Anal. Calcd for C114H136O26Si (1948.91): C, 70.20; H, 7.03. Found: C,70.37; H, 7.12.

4.15. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(2,3-di-O-methyl-b-D-glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyranosyl)-(1/4)-(6-O-tert-bu-tyldiphenylsilyl-2,3-di-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (24)

Compound 23 (550 mg, 0.28 mmol) was deprotected in ananalogous manner to that described for the synthesis of 16. Thecrude product was purified by silica gel chromatography (1:1 n-hexane/EtOAc) to give 24 (363 mg, 71%) as a colourless syrup; [a]D25

þ56.8 (c 0.06, CHCl3); Rf 0.40 (1:1 n-hexane/EtOAc); IR nmax (KBr):3445, 3063, 3029, 2930, 2858, 1624, 1496, 1454, 1428, 1363, 1326,1104, 1071, 1028, 913, 859, 822, 737, 699, 614, 505 cm�1; 1H NMR(CDCl3, 360 MHz): d¼7.73e7.11 (m, 45H, arom), 5.51 (d, 1H, J

2.9 Hz), 5.29 (d, 1H, J 2.9 Hz), 5.03e4.43 (m,16H, 7�CH2Ph, 2�H-1),4.24 (d, 1H, J 7.6 Hz), 3.88e3.75 (m, 14H), 3.40e2.88 (m, 16H), 3.62,3.57, 3.54, 3.49, 3.45, 3.43, 3.41, 3.27 (8�s, 24H, 8�OCH3), 2.07 (s,1H, OH), 1.05 (s, 9H, 3�t-Bu-CH3) ppm; 13C NMR (CDCl3, 90 MHz):d¼139.2, 138.9, 138.1, 137.8, 137.5, 132.8, 132.3 (9C, 9�Cq arom),135.4e126.6 (45C, arom), 102.5, 100.7, 98.1, 97.7, 96.5 (5C, 5�C-1),86.2, 84.5, 84.4, 83.2, 81.8, 81.5, 80.2, 79.7, 79.2, 78.9, 78.5, 76.9,74.0, 73.0, 71.0, 70.7, 70.4 (20C, skeleton carbons), 75.0, 73.2, 72.9,72.7 (7C, 7�CH2Ph), 68.9, 68.2, 67.1 (3C, 3�C-6), 62.8 (C-60), 61.6(C-6000), 60.5, 60.1, 59.9, 59.7, 59.3 (7C, 7�OCH3), 54.9 (C-1-OCH3),26.7 (3C, 3�t-Bu-CH3), 18.8 (Cq, t-Bu) ppm; MALDI-TOF (positiveion): m/z calcd for [MþNa]þ 1831.84. Found: 1831.91. Anal.Calcd for C103H128O26Si (1808.85): C, 68.34; H, 7.13. Found: C,68.47; H, 7.25.

4.16. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(2,3-di-O-methyl-b-D-glucopyranosyl)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyranosyl)-(1/4)-(2,3-di-O-methyl-a-L-idopyranosyl)-(1/4)-2,3,6-tri-O-benzyl-a-D-glu-copyranoside (25)

To a solution of compound 24 (350 mg, 0.19 mmol) in THF(2 mL) was added 1 M solution of (n-Bu)4NF (289 mL, 0.29 mmol).After 72 h, the mixture was concentrated and the residue waspurified by column chromatography (6:4 n-hexane/acetone) togive 25 (292 mg, 96%) as a colourless syrup [a]D25 þ61.4 (c 0.08,CH2Cl2); Rf 0.52 (6:4 n-hexane/acetone); IR nmax (KBr): 3465, 1638,1454, 1363, 1102, 1040, 739, 698 cm�1; 1H NMR (CDCl3, 360 MHz):d¼7.39e7.18 (m, 35H, arom), 5.52 (d, 1H, J 3.7 Hz), 5.15 (d, 1H, J3.4 Hz), 4.93e4.50 (m,16H, 7�CH2Ph, 2�H-1), 4.28 (d, 1H, J 7.8 Hz),3.93e3.63 (m, 15H), 3.62e3.15 (m, 12H), 3.61, 3.58, 3.54, 3.49, 3.44,3.42, 3.39, 3.35 (8�s, 24H, 8�OCH3), 3.03e2.94 (m, 3H), 2.36, 2.08(2�s, 2H, 2�OH) ppm; 13C NMR (CDCl3, 90 MHz): d¼138.7, 138.4,138.0, 137.8, 137.7, 137.5, 137.4 (7C, 7�Cq arom), 128.2e127.3 (35C,arom), 102.3, 98.6, 97.8, 97.0, 96.3 (5C, 5�C-1), 86.1, 84.4, 83.1, 82.6,81.5, 81.4, 80.1, 79.6, 79.2, 78.4, 75.2, 74.1, 73.9, 71.2, 70.8, 70.6, 70.1(20C, skeleton carbons), 75.5, 74.9, 73.2, 73.1, 72.7 (7C, 7�CH2Ph),68.1, 68.0, 67.4 (3C, 3�C-6), 61.6 (C-6000), 60.4, 60.1, 60.0, 59.6, 59.4,59.3, 59.2 (7C, 7�OCH3), 54.9 (C-1-OCH3) ppm; MALDI-TOF (pos-itive ion): m/z calcd for [MþNa]þ 1593.72. Found: 1593.81. Anal.Calcd for C87H110O26 (1570.73): C, 66.48; H, 7.05. Found: C, 66.56;H, 7.23.

4.17. Methyl (6-O-benzyl-2,3,4-tri-O-methyl-a-D-glucopyr-anosyl)-(1/4)-(sodium 2,3-di-O-methyl-b-D-glucopyr-anosyluronate)-(1/4)-(2,3,6-tri-O-benzyl-a-D-glucopyr-anosyl)-(1/4)-(sodium 2,3-di-O-methyl-a-L-idopyranosyluronate)-(1/4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (26)

Pentasaccharide 25 (310 mg, 0.20 mmol) was dissolved inCH2Cl2 (5 mL) and H2O (2.50 mL), and TEMPO (11 mg, 0.07 mmol)and BAIB (382 mg,1.19 mmol) were added at 0 �C. The solutionwasstirred vigorously for 24 h at room temperature. The reactionmixture was quenched by the addition of 10% aq Na2S2O3 solution(17 mL) and extracted with CH2Cl2 (3�25 mL), and the combinedorganic layers were dried, and concentrated. The crude productwas purified by silica gel chromatography (95:5 CH2Cl2/MeOH) togive 26 (306 mg, 94%) as a colourless syrup; [a]D25 þ6.3 (c 0.03,MeOH); Rf 0.38 (95:5 CH2Cl2/MeOH); IR nmax (KBr): 2919, 2359,1219, 1026, 772, 673 cm�1; 1H NMR (CD3OD, 360 MHz):d¼7.37e7.21 (m, 35H, arom), 5.41 (d, 1H, J 3.6 Hz), 5.21 (d, 1H, J5.5 Hz), 5.08 (d, 1H, J 3.4 Hz), 4.99 (d, 1H, J 10.8 Hz), 4.89e4.40 (m,16H), 4.02e3.95 (m, 2H), 3.88e3.63 (m, 12H), 3.61e3.30 (m, 2H),3.58, 3.52, 3.48, 3.45, 3.41, 3.36, 3.33 (8�s, 24H, 8�OCH3),3.29e2.94 (m, 9H) ppm; 13C NMR (CD3OD, 90 MHz): d¼140.3,139.8, 139.7, 139.6, 139.4 (7C, 7�Cq arom), 129.8e128.3 (35C,

M. Herczeg et al. / Tetrahedron 70 (2014) 2919e2927 2927

arom), 104.1, 101.1, 99.0, 97.9 (5C, 5�C-1), 86.9, 85.5, 84.4, 83.1, 81.1,81.0, 80.4, 80.3, 78.6, 77.8, 76.8, 72.1, 71.9, 71.7 (20C, skeleton car-bons), 76.6, 76.2, 74.6, 74.5, 74.1 (7C, 7�CH2Ph), 69.6, 69.4, 69.0 (3C,3�C-6), 61.2, 61.1, 60.9, 60.7, 60.3, 59.8, 55.6 (8C, 8�OCH3) ppm;MALDI-TOF (positive ion): m/z calcd for [MþNa]þ 1621.69. Found:1621.65. Anal. Calcd for C87H104Na2O28 (1642.65): C, 63.57; H, 6.38.Found: C, 63.60; H, 6.41.

4.18. Nona-sodium [methyl (2,3,4-tri-O-methyl-6-O-sulfonato-a-D-glucopyranosyl)-(1/4)-(2,3-di-O-methyl-b-D-glucopyr-anosyluronate)-(1/4)-(2,3,6-tri-O-sulfonato-a-D-glucopyr-anosyl)-(1/4)-(2,3-di-O-methyl-a-L-idopyranosyluronate)-(1/4)-2,3,6-tri-O-sulfonato-a-D-glucopyranoside] (idrapar-inux) (3)

Compound 26 (306 mg, 0.19 mmol) was dissolved in 96% EtOH/AcOH (19:1, 15 mL), and Pd(C) (10%, 134 mg) was added and stirredin an autoclave under a H2 atmosphere (at 10 bar) for 24 h. Thecatalyst was filtered off through a pad of Celite and the filtrate wasconcentrated under reduced pressure. The crude product was pu-rified by silica gel chromatography (7:6:1 CH2Cl2/MeOH/H2O) togive heptaol (171 mg, 91%) as a colourless syrup. Heptaol (144 mg,0.142 mmol) was treated with SO3$Et3N complex (901 mg,4.970mmol) in DMF (8mL). After 24 h stirring at 50 �C, the reactionmixture was neutralized with satd aq NaHCO3 (2.087 g,24.850mmol) and the resultingmixturewas concentrated in vacuo.The crude product was treated with Dowex ion-exchange resin(Naþ form), and then purified by Sephadex G-25 column chroma-tography eluting with H2O to give 3 as a white powder (193 mg,78%); mp: 210e215 �C (decomp.); [a]D25 þ5.0 (c 0.11, MeOH); (lit.13

[a]D25 þ55.0 (c 1, H2O); Rf 0.37 (6:7:1 CH2Cl2/MeOH/H2O)). Thespectroscopic and analytical data of 3 are consistent with thosegiven in the literature.13

Acknowledgements

The work is supported by the T�AMOP 4.2.4.A/1-11-1-2012-0001Project (National Excellence Program). The project is co-financedby the European Union and the European Social Fund. Financialsupport of the Hungarian Research Fund (K 105459) is alsoacknowledged.

Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.tet.2014.03.033.

References and notes

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5. Westerduin, P.; van Boeckel, C. A. A.; Basten, J. E. M.; Broekhoven, M. A.; Lucas,H.; Rood, A.; van der Heiden, H.; van Amsterdam, R. G. M.; van Dinther, T. G.;Meuleman, D. G.; Visser, A.; Vogel, G. M. T.; Damm, J. B. L.; Overklift, G. T. Bioorg.Med. Chem. 1994, 2, 1267e1280.

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